Human tuberculosis (TB) susceptibility is a complex and polygenic trait. The long-term objective of this research is to determine the extent of candidate genes in human innate immunity contributing to human TB susceptibility and the potential host-pathogen interactions. Our internationally collaborative team with a recently established TB sentinel surveillance network in China combines the resources of an ideal target population with an advanced investigative capacity to address the research objective. An important aspect of this study is to avoid the bias associated with our previous work in this field by utilizing several recent advances in Mycobacterium tuberculosis infection diagnosis. The following research lines are proposed. 1. The candidate gene-based association study has been considered more powerful than the linkage study in determination of genetic susceptibility to human complex disease such as TB. Two complementary approaches of the association study: the population-based case-control study and the family-based transmission-disequilibrium test (TDT), will be combined to explore associations between human TB susceptibility and candidate genes encoding M. tuberculosis extracellular receptors (toll-like receptors) and intracellular receptor (NOD2), which play an important role in human innate immunity against TB. 2. State-of-the-art molecular strategies will be used to conduct genome-level screening for common and rare nonsynonymous genetic variants in the candidate genes which are potentially associated with TB susceptibility in a previously unexplored target population. 3. All M. tuberculosis isolates from TB cases in this study will be molecularly characterized to test the hypothesis that distinct pathogen genotypes are nonrandomly associated with specific host genotypes. A particular interest will be placed on our recent finding in China, the "Shandong cluster", which is a widely disseminated M. tuberculosis cluster with increased likelihoods of drug-resistance and transmissibility. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is the most deadly infectious disease in the world, and accounts for 2 million deaths and 8 million new cases worldwide each year. TB control measures have been complicated by the increased prevalence of HIV/TB co-infection and drug-resistant bacteria. Our research at genome level will improve the understanding of the interaction between the host and pathogen, which may shed light on alternative strategies for TB treatment and prevention.